Alzheimer's disease (AD) is the most common form of dementia (loss of memory) in the elderly. The main pathological lesions of AD found in the brain consist of extracellular deposits of beta amyloid protein in the form of plaques and angiopathy and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein. Recent evidence has revealed that elevated beta amyloid levels in brain not only precede tau pathology but also correlate with cognitive decline. Further suggesting a causative role for beta amyloid in AD, recent studies have shown that aggregated beta amyloid is toxic to neurons in cell culture and has a detrimental effect on memory. This suggests that reducing beta amyloid levels is a viable therapeutic strategy for the treatment of AD.
Beta amyloid protein is composed mainly of 39-42 amino acid peptides and is produced from a larger precursor protein called amyloid precursor protein (APP) by the sequential action of the proteases beta and gamma secretase. Although rare, cases of early onset AD have been attributed to genetic mutations in APP that lead to an overproduction of either total beta amyloid protein or its more aggregation-prone 42 amino acid isoform. Furthermore, people with Down's syndrome possess an extra chromosome that contains the gene that encodes APP and thus have elevated beta amyloid levels and invariably develop AD later in life.
Methods of producing substituted heteroaryl sulfonamide compounds useful as beta amyloid inhibitors have been described [U.S. Pat. No. 6,610,734; U.S. Pat. No. 6,878,742]. These methods have included the construction of an acylated Evans oxazolidone chiral auxiliary, which is then converted to the corresponding enolate and electrophilically aminated with trisyl azide to afford the desired, key intermediate (J. Am. Chem. Soc. 109: 6881-6883 (1987)). The azide intermediate is then hydrolyzed to the a-azido acid and reduced to the chirally pure a-amino acid which can be converted to the corresponding N-sulfonyl 2-amino alcohols. However, this method utilizes reagents, notably, the trisyl azide, which are not suitable for large scale production.
What are needed are improved methods of making compounds that are effective in lowering beta amyloid production.